Accumulating evidence indicates that the incidence of HPV-associated neoplasia in HIV-positive individuals is substantially higher than in HIV-negative individuals despite effective antiretroviral therapy. These data strongly suggest that HIV may play a critical role in development of HPV-associated neoplasia of the anus, cervix and oropharyngeal cavity. However the mechanisms by which it does so are poorly understood. Our published work and preliminary data show that HIV may interact with oral and anal epithelia creating a tissue microenvironment where epithelial cells lose tight and adherence junctions. These epithelia have multiple changes consistent with epithelial-mesenchymal transition (EMT), a multistep epigenetic process characterized by loss of cell adhesion and increased mobility of epithelial cells. EMT is important in cell differentiation during embryogenesis but also plays a critical role in neoplastic progression. Our data show that oral and anal mucosal epithelial biopsies obtained from HIV-infected individuals show typical signs of EMT, i.e., the adherens junction protein E-cadherin is down-regulated and vimentin expression is up-regulated. Exposure of tonsil epithelial cells from HIV-uninfected individuals to HIV tat and gp120 proteins leads to induction of EMT. Additionally we observed that HIV infection is associated with elevation of proinflammatory cytokines tumor necrosis factor alpha (TNF-?) and interferon gamma (IFN-?) in mucosal epithelia, which may also be involved in induction of EMT. Finally, it is known that HPV oncoproteins E6/E7 can induce the EMT phenotype. Thus, there are several pathways through which HIV and HPV may interact with mucosal epithelia, and may synergize to establish EMT with consequent potentiation of HPV-associated neoplasia. In general the EMT phenotype is reversible and EMT cells may transition back and forth between EMT and the normal state, a process known as mesenchymal-epithelial transition (MET). Induction of MET or inhibition of EMT may represent a novel approach to prevention and treatment of HPV-associated oropharyngeal, cervical and anal neoplasia and may be a novel approach to reducing the high incidence of HPV-associated malignancy in HIV- infected individuals. Accordingly, our specific aims are: (1) To investigate mechanisms of HIV-associated EMT in cervical and anal mucosal epithelial cells and induction of MET in these cells by suppression of vimentin and upregulation of E-cadherin expression, (2) To investigate synergy between HIV and HPV in development of the EMT phenotype, and (3) To study the role of suppression of HIV- and HPV- induced EMT and activation of MET in the reduction of HPV-associated cervical and anal cell transformation and invasion. Knowledge generated through this work will be of great value to understanding the mechanisms by which HIV and HPV interact to potentiate development of HPV-associated epithelial neoplasia. This knowledge may also lead to development of compounds that may be useful for treatment of HPV-associated cancers and pre-cancers in the setting of HIV infection through inhibition of HIV/HPV-induced EMT and activation of MET.

Public Health Relevance

The goal of the proposed studies is to investigate the role of HIV in development of HPV-associated cervical and anal cancer. This work will greatly advance knowledge of the molecular mechanisms of HPV proteins tat and gp120, and proinflammatory cytokines tumor necrosis factor alpha and interferon gamma in promoting HPV-associated neoplasia. This research is highly relevant to public health since it may lead to novel therapies for HIV- and HPV-associated cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA232887-03
Application #
10057370
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2018-12-01
Project End
2023-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143